Five and six membered heterocyclic rings endowed with azobenzene as dual EGFR^T790M and VEGFR-2 inhibitors: design, synthesis, <i>in silico</i> ADMET profile, molecular docking, dynamic simulation and anticancer evaluations

Abstract

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine moieties have been developed and synthesized utilizing microwave and traditional methods. Our compounds were tested for growth inhibition of A549, MCF-7, HCT-116, and HepG2 tumors by dual targeting the VEGFR-2 and EGFR^T790M enzymes. The suggested compound's manner of binding with EGFR^T790M and VEGFR-2 active sites was explored through molecular design and MD modeling. The information from the results of the biological screening and the docking studies was highly correlated. The A549 cell line was the one that responded to the novel compound's effects most effectively. Having IC₅₀ values of 5.15, 6.37, 8.44 and 6.23 μM, respectively, 14 was the most effective derivative on the four A549, MCF-7, HCT116 and HepG2 cancer cells. It had greater activity than erlotinib and slightly inferior activities on the tested cell lines than sorafenib, respectively. The cytotoxicity of the most effective derivatives, 5, 6, 10 and 14, was evaluated against typical VERO cell lines. Having IC₅₀ values ranging from 42.32 to 55.20 μM, the results showed that the investigated drugs have modest toxicity against VERO normal cells. Additionally all derivatives were assessed for their dual VEGFR-2 and EGFR^T790M inhibitory effects. Among them, derivatives 14, 5 and 10 were established as the greatest inhibitors of VEGFR-2 at IC₅₀ values of 0.95, 1.25 and 1.50 μM correspondingly. As well, derivatives 14, 6, 5 and 10 could inhibit EGFR^T790M activity demonstrating strongest effects with IC₅₀ = 0.25, 0.35, 0.40 and 0.50 μM respectively. Furthermore, the ADMET profile was evaluated for compounds 5, 6, 10 and 14 in contrast to reference drugs sorafenib and erlotinib.